An increasing body of evidence suggests that vitamin D may reduce the risk of colorectal cancer and other cancers of the digestive system, acting through various proposed methods, including a reduction of pro- inflammatory factors. Blacks and African-Americans have virtually half the levels of 25(OH)D, the generally accepted best indicator of vitamin D status, compared to Whites. Differences in levels of plasma 25(OH)D could account for the greater incidence of colorectal cancer and other digestive system cancers in Blacks, particularly in the northeastern U.S., where solar UV-B intensity is low. The optimal dose of supplemental vitamin D needed to achieve adequate levels of plasma 25(OH)D is unknown, but it is likely to be much higher than currently recommended doses (400 lU/day). A critical need exists, particularly in Blacks, to define doses of oral vitamin D supplementation that will achieve a sufficient level of plasma 25(OH)D before vitamin D chemoprevention studies are initiated. We therefore propose to examine plasma 25(OH)D in an underserved population of Blacks living in the Boston area and establish a dose of vitamin D supplementation that will achieve a presumed protective level of plasma 25(OH)D levels in this cohort. First, following assessment of baseline plasma 25(OH)D levels, 320 participants will be randomized to placebo, 1000 ID, 2000 ID, or 4000 IU of vitamin D3 (cholecalciferol) per day in a 1:1:1:1 ratio. Then, after 3 months of supplementation, plasma levels of 25(OH)D will be determined. Secondly, we will examine if oral vitamin D supplementation reduces plasma levels of pro-inflammatory factors C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-aR2 (TNFaR2), and increases anti-inflammatory interleukin-10 (IL-10) levels. Thirdly, participants will be genotyped for relevant vitamin D pathway genes, and genotype prevalence will be compared to results from participants of the Nurses'Health Study and Health Professionals Follow-up Study, two cohorts for which we are separately funded to examine the influence of these genotypes on the risk of colorectal adenoma and cancer. We will also compare baseline 25(OH)D levels with Whites of these cohort members living in a similar latitude and who provided blood in the same season. We will also assess rise of 25(OH)D according to 25(OH)D-24-hydroxylase (CYP24) genotypes, as genetic variation in CYP24 as been proposed to contribute to lower 25(OH) in blacks. Results of this trial will help direct future randomized trials of vitamin D in the prevention of colorectal neoplasia and other cancers of the digestive system. In fact, once we define the optimal dose of vitamin D, our interdisciplinary team with expertise in disparities will be well positioned to lead an intervention trial that has major implications for efforts to address colorectal neoplasia disparities nationally.